The vascular embolization constitutes an important strategy for combating tumors, aneurysms and artery-venous malformations (AVMs). The technique consists of the finely divided material injection, via catheter, in the blood stream around the tumoral region, in such a way to obstruct mechanically the blood vessels that irrigates the damaged area. In this way, it is obtained an interruption in the nutrient supplying to the tumoral region; which tends to decrease, allowing a tissue recovery after a certain time interval (Kerber et al., 1978).
Since long time, different materials have been proposed in literature with the objective of occluding vascular channels of tumors and AVMs, within the context of embolization. Latchaw and Gold (1979) cite the utilization of metallic coils, silicone rubber, carbon micro-spheres and poly (vinyl alcohol) particles as materials useful in embolization. In all cases, one must observe the compatibility among the granulometry of the injected material and the catheter and vessels diameters, as well the material capacity of being subjected to sterilization procedures.
Among the above mentioned materials, is of note the poly (vinyl alcohol), PVA, which presents a series of interesting properties, such as a high compressibility, good elasticity, biodegradable, and good chemical resistance to acids, bases and detergents (Tadavarthy et al., 1975). In fact, the PVA foams have the capacity of compressing themselves and reassume the original format when in contact with blood, what makes PVA a material with high appealing to the embolization purposes, once the catheter size limits the size of the particles. However, the PVA presents a peculiar aspect in relation to the other polymeric resins, which is the absence of vinyl alcohol monomer in a free state. Basically, the PVA production occurs via hydrolysis or saponification of poly (vinyl acetate) (Marten, 1989). The PVA properties obtained in the hydrolysis depend strongly of the vinyl acetate polymerization step conditions (existence of ramification) and degree of polymer hydrolysis (moles of alcohol group in the chain). Is of note that vinyl acetate is a monomer with strong tendency to ramification during the reaction, resulting in a polymer with weak chemical resistance and highly susceptible to degradation during the hydrolysis step and conversion to poly (vinyl alcohol). To by-pass this obstacle, usually one gets help of performing tests in reduced temperatures, with utilization of alternative initialization mechanisms, as for example, application of ionizing light in ultra-violet region (Yamamoto et al., 1990). It is important to note the PVA synthesis with good solvent resistance and elevated thermal resistance, once the applied polymer as a material for embolization must be stable and resistant to sterilization procedures.
The PVA particles are normally produced from dissolution of PVAc in organic solvents (usually methanol) and posterior caustic treatment (usually employing soda, NaOH). In these conditions PVA is formed, which precipitates. The precipitated material has an irregular shape and presents typical morphology of flocs, as showed in FIG. 1. Thus, the usual process consists in PVAc production, PVAc purification, PVAc solubilization in caustic solvent, PVAc production, separate and purify PVA. It is proposed the PVA production with controlled morphology, as shown in FIG. 2, from vinyl acetate polymerization in aqueous suspension and PVA saponification in the aqueous suspension itself, simultaneously to the PVAc production or in a posterior step, using to this an alkaline aqueous medium.
Yamamoto et al. (1987) produced PVA from a classical PVAc saponification process in classical methanol. The PVAc was produced in emulsion, using a mercury light source to initialize the reaction. In the present invention the PVAc is produced in suspension and the saponification is carried out in-situ, in aqueous medium.
The U.S. Pat. No. 4,863,972 (Itagaki et al., 1989) claims a process to produce reticulate PVA particles, through PVA precipitation in alcoholic solution, being that, the proposed process does not depend on the preparation of PVA solution to particles formation.
Yamamoto et al. (1990) related the production of PVA from aqueous mixture of VAC and potassium persulfate, in presence of mercury light, being the reaction carried out in emulsion. In the process object of the present invention the reaction is carried out in suspension.
Kim and Lee (1992) related the preparation of PVA spherical particles with shell-and-nuclei structure. The particle is prepared from VAC polymerization in suspension, followed by saponification of the spherical PVAc in caustic aqueous medium, with posterior reticulation of PVA promoted by glutaraldehyde and saponification in caustic methanol. In the present invention neither the reticulation is necessarily done, nor the particles separation between different steps. The produced particles of the present invention can have PVA shell and nuclei with different reticulation degrees and yet, the nuclei in PVAc and the shell in PVA.
Derdeyn et al (1995) analyzed various marketed PVAs and showed that the irregular shape of the products and uncontrolled size particles were the main factors responsible for the catheter obstructions during embolization, these factors increasing considerably the risks of a surgical intervention. In the present invention, the produced particles have regular morphology and, therefore, allowing the reduction of risks associated to the embolization process.
Laurent et al. (1996) produced spherical particles with controlled morphology for embolization use. The particles, however, were formed with nuclei of trisacryl gelatin and shells formed by reaction of this gelatin with glutaraldehyde. In the present invention, PVAc forms the spherical particle nucleus and the shell is formed by PVA.
Beaujeux et al. (1996) observed that the use of spherical particles with controlled morphology enhances significantly the embolization performance, not only with respect to the reduction of catheter occlusions, but also with respect to the patient response to the treatment. They used, however, trisacryl gelatin particles in the study.
Lyoo et al. (1998) produced a high molecular weight PVA from the classical route of saponification in caustic methanol, using PVAc produced in suspension and in mass. It was used the azo compound ADMVN to effectuate the polymerization reaction at low temperature (30° C.). In the present invention it is not proposed the PVAc solubilization in caustic methanol to effectuate the hydrolysis.
The U.S. Pat. No. 6,160,025 (Slaikeu et al., 2000) claims an embolization method from PVAc solutions partially hydrolyzed and posterior precipitation in blood. The present invention does not propose the use of PVAc solutions to embolization, once the particles are already pre-formed.
Bendszus (2000) compared the embolization clinical performance conducted with trisacryl gelatin particles with controlled morphology, with commercial PVA of irregular morphology and came to conclusion that the clinical performances observed were similar.
The U.S. Pat. No. 6,191,193 (Kim et al., 2001) claims a process for spherical particles preparation of PVA/PVAc, with shell and nuclei structure, to posterior use as embolization agent. However, the process is based in the preliminary separation of PVAc particles produced in suspension by size range and posterior re-suspension of each size range for caustic treatment. Thus, the process of particles production is significantly more complex then the one here reported. Besides, the patent requires the use of methanol in the saponification medium and it does not report the clinical use of the particles produced for vascular embolization.
Mah et al. (2001) studied the PVA production from the classical process of PVAc saponification in caustic methanol, using, the VAc polymerization in emulsion started by a luminous source to produce the PVAc. They observed that the presence of oxygen might interfere in the reaction, obtaining products with lower molecular weight. In the present invention it is not proposed the PVAc solubilization in caustic methanol to effectuate the hydrolysis. Besides, the PVAc is produced in suspension.
Lyoo and Lee (2002) propose a PVA preparation method in a single batch, from VAc polymerization in suspension. The technique consists in addition of caustic methanol mixtures to the reaction medium after polymerization and conduction of saponification for two (02) days. The present invention does not require the use of caustic methanol and is capable of producing particles with shell-and-nuclei morphology with a saponification time much lower, in hour scale.
Wan et al. (2003) prepared PVA porous particles from cross-reactions initialized by epichloridrine in aqueous solutions and in inverse suspensions in paraffin. In the present invention it is not used reticulation agents, nor inverse suspensions of PVA aqueous solutions in paraffin.
In the U.S. Pat. No. 6,531,111 (Whalen et al., 2003) is claimed a polymer solution constitute for a biocompatible polymer, biocompatible solvent and contrast, in which the polymer precipitates to form particles used in embolization. The present invention does not presuppose the formation of PVA solutions to posterior precipitation.
The U.S. Pat. No. 6,627,600 (Boutignon, 2003) claims the use of PVA particles to impregnate medicaments and use for controlled liberation. In the present invention, the particles have a shell-and-nuclei structure, with PVAc nuclei and PVA shell.
Its important observe that the PVA particles commercially available and produced by saponification conventional processes in caustic methanol present the following disadvantages:                “Flocculated” aspect, as illustrated in FIG. 1;        Highly irregular surface, as illustrated in FIG. 1;        Ease of agglutination and aggregation;        Difficulty of passing through the angiographic catheter due to the irregular morphology illustrated in FIG. 1;        Susceptibility to degradation (biodegradation);        Future rechanneling of the treated vascular bed;        Costs too high.        
The poly (vinyl alcohol) is obtained after poly (vinyl acetate) saponification. Due to the vinyl alcohol monomer tautomerism, one does not get to produce PVA by direct polymerization. The vinyl acetate polymerization can be effectuated in different ways. In the present invention, the vinyl acetate polymerization is effectuated in suspension, a process where the monomer, which is relatively insoluble in water, stays disperse in drops in a medium that has an initiator and a stabilizing agent. This agent stops the drops coalescence and dispersion during polymerization, reducing the interfacial tension and forming a superficial layer around the drop. In such a manner, the partially formed particles agglomeration is avoided and the particle spherical shape is preserved (Wood et al., 1997). The polymerization occurs in the monomeric phase and in most cases occurs by the way of a free radical mechanism. To avoid decantation and foam, agitation is used during the entire reaction. The type and velocity of the agitator employed, the dimensions and reactor geometry, the volumetric fraction of the monomeric phase and the type and concentration of the suspension agent employed influence the particles size distribution. The particle morphology is an important characteristic for the product formed application. Generally, in the polymerization in suspension the formed particles possess a pearl shape, with diameters in the range of 5-1000 μm (Dowding and Vicent, 2000).
In the saponification occurs the substitution of the acetate group for the hydroxyl group. It is used to this end solutions of strong acids or bases, generally sodium hydroxide (NaOH) solutions. The PVAc particle stays disperse in an aqueous medium under agitation, until the base addition and the reaction initialization.
After saponification the formed product possess a hydrolysis degree, also known as saponification degree, which represents the number of hydroxyl groups present in the molecule. A manner to determine the hydrolysis degree of formed PVA is from the ratio of methyl and methylene protons peaks of the hydrogen spectrum of NMR (Nuclear Magnetic Resonance). The PVA that presents a hydrolysis degree of about 81% possess a particular interest: it is the material that possesses the major solubility in water (Sandler et al., 1998).
The PVA possess varied utilization. Among them is of note its use as adhesives, as agents of suspension in polymerization, as agent for vascular embolization and as a film for instantaneous liberation cover in pills. Such a huge variety of application is owned to properties as the biocompatibility, the biodegradability, the good elasticity, the compressibility, among others (Marten, 1989). Due to these properties, the PVA is a strong appealing material for use in embolization procedures. However, the commercial sold products are presented as foam, not having a defined shape (Lacthaw and Gold, 1979).
With the present invention it is proposed viable routs of PVA/PVAc particles synthesis with shell-and-nuclei controlled morphology, aiming its application in vascular embolization. Classical polymerization procedures of vinyl acetate in hot and cold suspension are considered, followed by non-conventional hydrolysis via aqueous basic solutions and final steps of particles superficial treatment and purification promoted by radiation.